The goal of this project has been to examine the central nervous system effects of changes in reproductive endocrine function occurring in the context of hypogonadism. Investigations have been primarily focused on the characterization of affective disorders occurring during the perimenopause and midlife, the identification of the role of gonadal steroids in these mood disorders, and the examination of the neuroregulatory consequences of the presence and absence of gonadal steroids in women and men. Finally, the information obtained by these protocols will help identify the predictive utility of endocrine measures in perimenopausal depression and help define the role of hormonal therapies in mood disorders occurring at midlife in men and women. Findings to date: 1) a significant improvement in measures of depression and libido after DHEA administration was seen in 46 men and women with midlife-related major and minor depression; 2) neither gender nor plasma hormone levels predicted the therapeutic response to DHEA administration in midlife-related depression; 3) neither short term (six week) nor long term (six months-one year) administration of DHEA significantly altered measures of bone metabolism or bone density; 4) seven of 13 depressed perimenopausal women have experienced a remission of their depression during participation in a double-blind placebo-controlled trial of estradiol, phytoestrogens, and SERMs; 5) the SERM raloxifene was associated with an increase in plasma estradiol levels and a remission of mood symptoms in three (of three) perimenopausal depressed women. In a study involving the induction of hypogonadism in men and women with GnRH agonists, we have observed the hypogonadal state to be associated with the following: 1) the development of clinically significant mood symptoms in approximately 10% of hypogonadal men despite the presence of hot flushes and loss of libido in 90-100% of these men; 2) baseline evaluations of sexual functioning but not plasma hormone levels predicted the degree to which sexual function was decreased after induced hypogonadism in both men and women (higher baseline sexual functioning was associated with greater declines in libido during hypogonadism); 3); CSF measures of the neurosteroid androsterone but not testosterone correlate with sexual function in men during both hypogonadism and testosterone replacement; and 4) the elimination in women of both cognition activated regional cerebral blood flow (O15 3D PET scans) in the dorsolateral prefrontal cortex and the reciprocal functional connectivity between the left hippocampal formation and the contralateral dorsolateral prefrontal cortex compared to either estradiol or progesterone replacement. In collaboration with NICHD we have observed that women with Turner Syndrome (n = 100) have significantly higher scores on measures of shyness, depression and anxiety than asymptomatic controls (n = 35) but their scores do not differ from those in women with premature ovarian failure (POF) (n =100). Finally, women with POF report an increased frequency of past episodes of depression compared to community samples of women, and the majority of these depressive episodes occurred in the context of menstrual cycle irregularity preceding their final menstrual period and the diagnosis of POF.